PROJECT SUMMARY Organisms with extreme phenotypes provide a special window into the evolutionary process. Compared to their mainland relatives, populations on islands often exhibit exceptional body sizes. Among mammals, insular populations of small-bodied species tend to evolve larger sizes, whereas bigger species tend to get smaller, a phenomenon known as the ?island rule?. This pattern raises the intriguing possibility of a common evolutionary mechanism, but its genetic basis remains mostly uncharacterized. With multiple independent examples of substantial size increase on islands, historical records of colonization, and an expansive genetic toolkit, house mice offer a promising model system for understanding the genetics of the island rule. The largest wild house mice in the world reside on Gough Island, a remote island in the middle of the South Atlantic Ocean. In just a few hundred generations, mice on Gough Island evolved to be twice the size their mainland relatives. During the first funding period of our R01 (?The Genetics and Evolution of Extreme Body Size in Mice from Gough Island?), we identified quantitative trait loci (QTL) ? including anatomically global size regulators ? responsible for this remarkable case of rapid evolution. The proposed research, a renewal of that project, will build strategically on our progress in two directions. First, we will functionally characterize and fine- map QTL for body size in Gough Island mice ? two necessary steps toward identifying the causative genes and mutations. We will use congenic strains to evaluate QTL effects on intermediate phenotypes that play key roles in growth and we will use sub-congenic strains to refine QTL intervals to contain manageable numbers of candidate genes. Second, we will map QTL for extreme body size evolution in a second island population from Papa Westray. By comparing QTL in mice from Papa Westray and Gough Island, we will determine whether independent instances of the island rule share genetic properties. The powerful combination of functionally characterizing individual QTL with comparative mapping of the overall genetic architecture will generate key insights into complex trait evolution and phenotypic convergence in nature. This project will reveal the genetic determinants of a common evolutionary phenomenon. In humans, body size variation is connected to risk for a plethora of common disorders, including cancer, cardiovascular disease, obesity, and diabetes. The proposed research will benefit genetic studies of human disease by developing and characterizing mouse models of naturally occurring size variation. 1